The somatosensory system mediates pruritus, or itch, the unpleasant sensation that evokes a desire to scratch. Acute pruritus serves an important protective function by warning against harmful agents in the environment such as insects, toxic plants or other irritants. Pruritus can also be a debilitating condition that accompanies numerous skin, systemic, and nervous system disorders. While many forms of itch are mediated by histamine signaling, recent work by us and others makes clear that additional key neural pathways are at play. Mast cells release a variety of puritogens that mediate allergy-evoked itch, psoriasis and eczema, and anti-histamines are not always effective in treating the full spectrum of allergic disorders. Likewise, most chronic itch conditions are insensitive to antihistamine treatment. For many itch disorders, therapeutic targets for treatment have yet to be identified. In light of the need for novel drug targets, the goal of this proposal is to identify genes and biomolecules that underlie itch, focusing on signaling mechanisms in primary afferent neurons and spinal cord modulatory interneurons. Somatosensory afferents are activated by itch-producing compounds that are released by a variety of cells in the skin. Pruritogens trigger somatosensory neuron activation by binding to G-protein coupled receptors and opening transduction channels that depolarize the nerve terminal and promote action potential firing; these neurons then signal to itch-specific neurons in the spinal cord. While recent studies have begun to delineate the basic characteristics of the itch circuit, the molecular mechanisms underlying itch have yet to be identified: the receptors, transduction channels and downstream signaling factors are largely unknown, in both primary afferents and spinal neurons. This grant proposal describes the development of new genetic approaches to meet this challenge. We are two biologists with experience and expertise in sensory neurobiology, genetics, and genomics who seek to identify the genes that drive itch behaviors. We will analyze the natural variation between genetically distinct mouse strains in itch-evoked behaviors and identify sequence and gene expression differences that underlie such phenotypic change. In contrast to traditional genetic screening approaches, which are not easily applicable to live-animal phenotypes in the mouse, the genetic mapping paradigm has the potential to survey a genome's worth of genetic perturbations and uncover novel determinants of itch. Identification of candidate itch factors will provide new targets for development of drugs and therapies to treat intractable itch. !